Compounds and methods of arylmethylation (benzylation) as protection for alcohol groups during chemical synthesis

ABSTRACT

A process for benzylating an alcohol includes mixing 2-benzyloxy-1-methylpyridinium triflate in an aromatic hydrocarbon solvent having a predetermined boiling point; adding an acid scavenger to the mixture; combining the alcohol to be benzylated with the mixture; reacting the alcohol with the 2-benzyloxy-1-methylpyridinium triflate by heating above ambient temperature to generate the benzylated alcohol; and separating the benzylated alcohol from the mixture.

RELATED APPLICATION

This application claims priority from provisional application Ser. Nos.60/668,699, filed on Apr. 6, 2005, and 60/708,580, filed on Aug. 16,2005, both of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to the field of chemical organic synthesisand, more particularly, to compounds and methods for benzylation andarylmethylation of alcohol groups as protection of the alcohol groupduring chemical synthesis.

BACKGROUND OF THE INVENTION

The complexities of natural product synthesis and of the rapidlydeveloping field of carbohydrate synthesis create a demand forchemically differentiable protecting groups (PGs) for vulnerablefunctionality. Benzyl ethers are among the most popular alcohol Pgs dueto their ease of formation, stability to a wide range reactionconditions, and mild cleavage protocols. Modified arylmethyl PGs havebeen tailored for use in more complex systems.

Several arylmethyl PGs are cleaved by initial transformation into apara-hydroxbenzyl (PHB) ether. Jobron and Hindsgaul first reported theuse of O-protected 4-O-benzyl PGs for carbohydrate chemistry. Removal ofthe arene 4-O-PG under the appropriate conditions reveals the PHB ether,which is then easily hydrolyzed. Cross-coupling of para-bromobenzyl(PBB) ethers provides a similar effect: palladium-catalyzed amination ofthe PBB group yields a labile para-aminobenzyl ether, whereaspalladium-catalyzed borylation of PBB followed by oxidation afforded aPHB ether in a synthetic approach to ciguatoxin.

These past efforts reflect the importance of diverse arylmethyl PGs andhighlight the need for orthogonality and functional group compatibilityin the cleavage event.

As noted above, benzyl ethers are among the most common and importantprotecting groups in organic synthesis. Like other alkyl ethers, theyare advantageous for their stability to a wide range of reactionconditions and for the minimal electronic impact that they impart on theoxygen atom to which they are attached. For example, benzyl ethers areoften employed to establish chelation control during addition to chiralaldehydes, which provides selectivity opposite that predicted by theacyclic Felkin-Anh model and observed with bulky silyl ethers.Similarly, benzyl-protected glycosyl donors are “armed” relative toacylated analogues. Among alkyl ethers, benzyl (and modifiedarylmethyl)ethers are perhaps the most versatile with respect to modesof cleavage, which include hydrogenolysis, oxidation, and acidicdecomposition under a range of experimental protocols.

Relatively harsh conditions are typically required for generating benzylethers from the corresponding alcohol, with the two most popularprotocols being (1) the Williamson ether synthesis, an SN2-type reactionbetween alkali metal alkoxides and benzyl bromide, and (2) couplingusing benzyl trichloroacetimidate, which is generally promoted bytrifluoromethanesulfonic acid (triflic acid, TfOH). Typical benzylationreactions are thus limited to substrates that tolerate either stronglyacidic or basic conditions. (β-Hydroxy esters, for example, are subjectto several acid- or base-catalyzed reactions, including retro-Aldol,elimination, and epimerization of stereogenic centers-to the carbonylgroup. Benzylation of these ubiquitous intermediates in the synthesis ofpolyketides and other important compounds can be problematic. Selectiveprotection of polyol systems (e.g., carbohydrates) can also becomplicated by base-catalyzed migration of esters and silyl ethers andby acid-catalyzed cleavage of silyl ethers and acetal linkages.

A recent review addresses the myriad options for protecting alcoholsusing mild, convenient, and environmentally friendly conditions, but nomethods for the formation of benzyl ethers are discussed. Silylation andacylation of alcohols can be accomplished under effectively neutralconditions using activated reagents that react with the free alcohol.Imidazole and DMAP are frequently employed to activate silyl and acylchlorides; conveniently, they are also capable of scavenging any acidthat is produced during the course of the reaction. Protonation ofbenzyl trichloroacetimidate provides an activated reagent that reactswith free alcohols, but this mode of activation precludes neutralizationof free acid. In principle, covalent activation (alkylation) of atrichloroacetimidate surrogate would enable the formation of benzylethers in the absence of external base or acid and in the presence ofacid scavengers (if desired).

Accordingly, benzylation of alcohols under mild and nearly neutralconditions, as disclosed herein, would constitute a significant advancein synthetic chemistry. Thus, it was envisioned that 2-benzyloxypyridinecould serve as an imidate surrogate for benzylation of alcohols.Pyridinium salts have been employed in esterification reactions, withMukaiyama's 2-chloro-1 methylpyridinium iodide being perhaps the mostpopular.

Conversion of alcohols into thioesters and azides using2-fluoro-1-methylpyridinium tosylate has also been demonstrated. The twopieces of prior knowledge that were most influential in guiding thecurrent work are: (1) certain 2-alkoxypyridinium bromides decompose tobromoalkanes and pyridones; and (2) 2-alkoxypyridinium sulfonates do notproceed spontaneously to alkyl sulfonates. It was hypothesized thatdecomposition of 2-alkoxypyridinium sulfonates in the presence ofalcohols would give rise to alkyl ethers and pyridones, and preliminarydata in support of this hypothesis was reported from this laboratory.

SUMMARY OF THE INVENTION

With the foregoing in mind, the present invention advantageouslyprovides compounds and methods for benzylation of alcohol groups as ameans of protection of the alcohol group during chemical synthesis.

This laboratory recently reported that aryl-siletanes(-silacyclobutanes) react with hydrogen peroxide under mild conditionsto afford phenols. See the publication by Sunderhaus, J. D.; Lam, H. andDudley, G. B.; Oxidation of Carbon-Silicon Bonds: The Dramatic Advantageof Strained Siletanes; Org. Lett. 2003, 5, 4571-4573; which isincorporated herein by reference in its entirety. The oxidation reaction(silylarene to phenol) dramatically increases the oxidation potential(electron density) of the arene ring.

Seeking to take advantage of this change, it was an object to develop anew arylmethyl PG for alcohols, the cleavage of which would be triggeredby hydrogen peroxide. Unlike masked PHB ethers, latent PHB ethers offergreater promise in terms of orthogonality with a range of other commonPGs. for example, revealing the PHB intermediate does not involvecleavage of a different protecting group.

Herein disclosed is the synthesis and application of asiletane-substituted benzyl PG for alcohols and phenols, as shown inFIG. 1. Para-Siletanylbenzyl (PSB) derivatives 1a and 1b were preparedfrom commercially available compound 7 according to FIG. 2.

Also disclosed are the synthesis and reactivity of2-benzyloxy-1-methylpyridinium triflate (compound 1), a novelbenzylation reagent for alcohols. Salt 1 is easy to prepare,bench-stable, and pre-activated. No acidic or basic promoters are neededfor benzyl transfer, which occurs simply upon warming in the presence ofthe alcohol substrate.

Typical prior art benzylation protocols are shown in FIG. 6, wherein theobjective of the present invention is indicated in the lower structuralformula shown.

Herein are described the synthesis and reactivity of 2-benzyloxy-1methyl-pyridinium triflate (Bn-OPT, 1), which provides benzyl etherssimply upon warming in the presence of a free alcohol. The overallbalanced equation for the benzylation of alcohols (2→3) is shown in FIG.7. Oxypyridinium triflate 1 may eventually supplant benzyltrichloroacetimidate for the synthesis of benzyl ethers from alcohols.

BRIEF DESCRIPTION OF THE DRAWINGS

Some of the features, advantages, and benefits of the present inventionhaving been stated, others will become apparent as the descriptionproceeds when taken in conjunction with the accompanying drawings,presented solely for exemplary purposes and not with intent to limit theinvention thereto, and in which:

FIG. 1 is an overview of protection/deprotection of alcohols using thepara-siletanylbenzyl protecting groups, according to an embodiment ofthe present invention;

FIG. 2 shows preparation of 1a and 1b: (i) HCl, MeOH, 3 h, 94% (1a);(ii) CBr₄, PPb₃, 12 h, 95% (1b);

FIG. 3 depicts alcohols and PSB ethers described in Tables 1 and 2;

FIG. 4 shows a two-step protection of alcohols and its overall yields;

FIG. 5 indicates orthogonality in the oxidative cleavage ofpara-siletanylbenzyl (PSB) and para-methoxybenzyl (PMB) ethers;

FIG. 6 shows standard prior art benzylation protocols (above) and oneapproach of the present invention (below);

FIG. 7 illustrates the balanced equation for benzylation of alcohols;

FIG. 8 shows the reaction for synthesis of compound1,2-benzyloxy-1-methylpyridinium triflate;

FIG. 9 shows byproduct compounds in the reaction shown in Table 3;

FIG. 10 shows a reaction for benzylation of chiral β-hydroxy ester 2e;

FIG. 11 depicts a benzylation reaction according to the presentinvention in the presence of a primary silyl ether;

FIG. 12 shows proposed mechanisms for the benzylation according to anembodiment of the present invention; and

FIG. 13 in the top panel shows the reaction according to the presentinvention and in the lower panel shows a similar reaction but whichfails to produce the desired end product.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will now be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionpertains. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, suitable methods and materials are described below. Anypublications, patent applications, patents, or other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including any definitions,will control. In addition, the materials, methods and examples given areillustrative in nature only and not intended to be limiting.Accordingly, this invention may, however, be embodied in many differentforms and should not be construed as limited to the illustratedembodiments set forth herein. Rather, these illustrated embodiments areprovided so that this disclosure will be thorough and complete, and willfully convey the scope of the invention to those skilled in the art.Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

Para-Siletanylbenzyl (PSB) Ether as a Benzylating Protective Group.

Herein disclosed is a novel arylmethyl protecting group that iselectonically similar to benzyl (Bn) but that can be cleaved under mildoxidizing conditions in the presence of para-methoxybenzyl (PMB).para-Siletanylbenzyl (PSB) ethers are formed in one or two steps fromthe corresponding alcohols and cleaved in one or two steps with basicperoxide. Alcohols and phenols have been protected in good yields anddeprotected cleanly under mild oxidative conditions, for example, withhydrogen peroxide.

Arylmagnesium bromide, compound 6 in FIG. 2, couples with siletane 7 toprovide 8 in excellent yield. The silyl ether is then selectivelyremoved in acidic methanol to afford PSB alcohol 1a. The fact that thearylsiletane is unaffected by these conditions is encouraging withrespect to the potential utility of PSB ethers. PSB—OH (1a) then yieldsPSB—Br (1b) upon treatment with CBr₄ and PPh₃.

We selected a representative sample of aromatic and aliphatic alcoholsto serve as test cases for the formation and cleavage of PSB ethers andthese can be seen in FIG. 3.

Protection of phenols can be achieved using PSB—OH (1a) under Mitsunobuconditions (Table 1, entries 1 and 4). Those of skill in the art willrecognize that the term “Mitsunobu conditions” is explained in Hughes,D. L.; Org. React. 1992, 42, 335-656; a publication which isincorporated herein by reference in its entirety. Attempts to alkylatepotassium, cesium, or sodium salts with 1b were unsuccessful (entries 2and 6). Arylmethylation of primary alcohols (i.e., 2c) occurs smoothlywith PSB—Br (1b) using freshly prepared Ag₂O; this afforded thecorresponding PSB ether in 80-83% yield (entry 5). However, secondaryalcohols could not be protected efficiently using the same method evenafter prolonged reaction times (entries 7 and 8). Side products and/orlow conversions were observed.

A two-step protection strategy was adopted for such substrates (FIG. 4).The alcohol is first derivatized as a PBB ether, which is then silylatedvia the corresponding Grignard reagent. This circumvents the independentsynthesis of 1 and increases the scope of PSB protected alcohols. Thealternative protocol may be useful for protection of alcohols prior tointroducing sensitive functionality.

With PSB ethers in hand, the deprotection was investigated usingconditions identified previously in our laboratory. Tamao-type oxidationof aryl ethers in 3a and 3b provides the deprotected phenols (2a and 2b)in one step (Table 2, entries 1 and 2). Intermediate PHB ethers 4a and4b undergo solvolysis during the course of the reaction.

In the aliphatic ether cases (3c-e), the labile PHB ethers (4c-e) wereisolated and then cleaved using FeCl₃ (entries 3-5, 7) or DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone; entry 6) to give alcohols2c-e. Alternatively, Woerpel's more rigorous carbosilane oxidationprotocol also affords the PHB ethers (4c and 4d, entries 6 and 7). Suchconditions are not expected to tolerate pendant silyl ether PGs, butthey do afford excellent yields after a relatively simple purification.PSB ethers can also be removed by hyrdogenolysis (entry 8).

PSB ethers are presumably similar to benzyl ethers in terms of areneoxidation potential, yet they cleave under mild oxidizing conditionsthat are unique among the common arylmethyl PGs. This attractive featureis shown herein through competition experiments with para-methoxbenzyl(PMB) ether 10. PMB ethers can be removed oxidatively with DDQ in thepresence of Bn ethers; the same orthogonality is seen with PSB ethers(FIG. 5). Alternatively, treating an equimolar mixture of 3c and 10 withbasic peroxide affects only the PSB ether, leaving the PMB group intact.

Thus, the para-siletanylbenzyl PG has been shown to protect phenols andprimary alcohols cleanly. It's easy removal under mild oxidativeconditions as well as its orthogonality with the PMB group can beadvantageous in multi-step synthesis.

2-Benzyloxy-1-methylpyridinium triflate as a benzylating ProtectiveGroup Synthesis and Isolation of pyridinium salt 1

The synthesis of 1 is illustrated in FIG. 8. Benzyl alcohol is coupledwith 2-chloropyridine using a modification of a reported procedure toafford 2-benzyloxypyridine, compound 5, in high yield. A range ofalkylating agents and solvents was investigated in search of preferredconditions for the irreversible covalent activation of 5. The preferredprotocol is to add methyl triflate (bp 94-99° C.) to an ice-coldsolution of compound 5 in toluene and allow the mixture to warm toambient temperature. A white microcrystalline solid, compound 1, formswithin minutes, as the solution warms. Analytically pure compound 1 (mp82-86° C.) can be isolated by filtration or by evaporation of thesupernatant under reduced pressure. Salt 1 is remarkably stable. It maybe preferably stored under an argon atmosphere either in a refrigeratoror on the laboratory bench-top at room temperature and the whitecrystals of compound 1 are routinely handled open to the air. Nodifferences have been observed between freshly prepared crystals andthose that were prepared three months prior.

Development and Analysis of a Benzylation Protocol.

At room temperature, the title reagent is freely soluble in chlorinatedsolvents such as dichloromethane, chloroform and dichloroethane; it ispartially soluble in ethereal solvents such as THF and ether; and it isinsoluble in aromatic hydrocarbons such as benzene and toluene.Solutions of compound 1 and 3-phenylpropanol, 2a as shown in Table 3,provided the desired benzyl ether upon heating. Because of its abilityto solvate compound 1 and its convenient boiling point (83° C.), theinitial investigation of reaction conditions was conducted indichloroethane (DCE).

A first consideration was the presumed mild acidity of hydroxypyridiniumtriflate 4 (Table 3). Among the various acid scavengers investigated,heterogeneous inorganic salts appeared most compatible with the desiredbenzylation reaction (Table 3, entries 3-5). Soluble amines appeared tointerfere with the coupling reaction (Table 3, entries 1 and 2) and itwas unclear whether external amine bases would present any advantage interms of moderating the potential acidity of pyridinium, compound 4.Based on these results and a cost analysis, magnesium oxide (MgO)emerged as a preferred choice. Thereafter, MgO was routinely included inall subsequent experiments.

In addition to the desired benzyl ether, two byproducts were observed inthe crude product mixture, as seen in FIG. 9: 1-methyl-2-pyridone(compound 6) and dibenzyl ether (Bn₂O, compound 7). Pyridone 6, theconjugate base of hydroxypyridinium 4, is the expected byproduct ofbenzylation reactions using compound 1. Pyridone 6 is freelywater-soluble and easily removed by aqueous extraction. The source ofBn₂O is not fully understood but it is thought that it may derive fromreaction of compound 1 with MgO, although small amounts of 7 were alsoobserved during control experiments that did not include MgO. It istheorized that adventitious moisture may be partly responsible for theformation of 7. Because dibenzyl ether is unlikely to interfere withmost benzylation reactions, presence of a small amount of this byproductis not considered to be a serious concern. Nonetheless, it was difficultto separate 7 from many of the alkyl benzyl ethers generated during thecourse of these investigations.

A test indicative of the efficacy of compound 1 in the invention was thebenzylation of chiral β-hydroxy ester 2e (seen in the formula of FIG.10). Benzyl ethers derived from such chiral alcohols are difficult toobtain under Williamson ether conditions because of the potential bothfor β-elimination and/or for epimerization of the labile stereogeniccenter α-to the ester. Benzylation using compound 1 proceededefficiently (2e→3e) with no evidence of epimerization detectable bychiral HPLC analysis. Benzyl ether 3e was easily separated from Bn₂O bychromatography on silica gel. A series of primary and secondary alcoholswere benzylated under similar conditions and with similar efficiencies(70-76% yield). These results were reported by Poon, K. W. C.; House, S.E. and Dudley, G. B., in Synlett 2005, 3142-3144, which publication isincorporated herein by reference in its entirety.

Despite limited solubility, mixtures of compound 1 in many solventsbecame homogeneous upon warming, especially as the temperaturesapproached the melting point of compound 1 (82-86° C.). Toluene emergedas a promising preferred solvent in small-scale exploratory experiments.Therefore, various aromatic solvents, as shown in Table 4. Yieldsimproved significantly in aromatic hydrocarbon solvents relative todichloroethane (>90% vs. 67%).

Reactions conducted in toluene and, to a lesser extent, benzene andchlorobenzene, gave rise to trace amounts of benzylated solventmolecules (FIG. 12). No such products were observed from reactionsconducted in benzotrifluoride (α,α,α-trifluorotoluene, PhCF₃).

In addition to being an excellent solvent for the present benzylationreactions, benzotrifiuoride is low-cost, moderately volatile (bp100-103° C.), and highly regarded as an environmentally friendlyalternative to chlorinated solvents. Benzotrifluoride is the preferredchoice as solvent for the benzylation reactions, although Table 4indicates that other aromatic hydrocarbons are also suitable and theseare intended to be included within the scope of the invention.

Having identified a preferred solvent, acid scavenger, and time andtemperature, the scope and limitations of what are considered to be mildand effectively neutral benzylation conditions was explored. Thetolerance of this protocol for sensitive functionality was indicated bya test of the herein disclosed benzylation reaction in the presence of aprimary silyl ether, as shown in FIG. 11. The desired benzyl ether,compound 3a, was obtained in excellent yield and silyl ether, compound8, was recovered unchanged.

Mix and Heat Benzylation of Alcohols: Scope and Limitations.

Table 5 illustrates the benzylation reactions of representative alcoholsunder preferred conditions as disclosed herein. Primary (entries 1-6)and secondary (entries 7-9) alcohols all provided the desired benzylethers (3a-h) in good to excellent yield. Among these substrates are anallylic alcohol (entry 4), a homo-allylic alcohol (entry 9), and aβ-hydroxy ester (entry 6). No difference was detected between freshlyprepared reagent and a sample of 1 that had been aged for three months(cf. entries 1 and 2).

Tertiary alcohols and phenols provided variable results (entries 10-12).1-Adamantanol (2i), which is not prone to elimination, afforded benzylether 3i in good yield. Tertiary benzylic alcohol 2j, which is highlyprone to elimination, provided only a moderate yield of ether 3j. Thesetwo substrates may approximate the upper and lower limits of benzylationefficiency for tertiary alcohol substrates using 1. Phenols (e.g., 2k,entry 12) reacted sluggishly in these tests, possibly due to a decreasein nucleophilicity relative to aliphatic alcohols. Because benzylationof phenols can be accomplished using Mitsunobu conditions, 19 this classof substrates was not investigated further.

Insights into the Potential Reaction Mechanism.

Without wishing to be bound thereby, the mechanistic course ofbenzylation reactions using 1 probably falls along the continuum betweenSN1 and SN2 pathways, as shown in FIG. 12. Although no detailed kineticstudies have been conducted, two key observations are more consistentwith an SN1-type mechanism. Benzylation reactions conducted in tolueneafforded trace amounts of o-12 and p-12. It is assumed that thesecompounds derive from Friedel-Crafts alkylation of toluene, whichsuggests the presence of benzyl cation (compound 9 in FIG. 12) in thereaction mixture and argues in favor of an SN1-type pathway.Methoxypyridinium salt 10 was completely inert under similar conditions,which argues against an SN2-type pathway. It is, therefore, concluded,again not wishing to be bound thereto, that benzylation using compound 1is more likely to occur via the SN1 mechanism. This conclusion isconsistent with behavior observed in trichloroacetimidate reactions.

EXPERIMENTAL DETAILS Synthesis of 2-Benzyloxypyridine, Compound 5 asShown in FIG. 8

The following is a modification of a previously reported procedureaccording to a publication by Serio Duggan, A. J.; Grabowski, E. J. J.;and Russ, W. K. Synthesis 1980, 573-575. Said publication beingincorporated herein by reference in its entirety. A mixture of benzylalcohol (2.00 g, 18.5 mmol), 2-chloropyridine (3.46 g, 30.5 mmol), KOH(3.42 g, 61.0 mmol, ground with a mortar and pestle), toluene (37 mL),and 18-crown-6 (24.4 mg, 0.925 mmol) was heated at reflux for 1 h withazeotropic removal of water (Dean-Stark trap). The reaction mixture wasthen cooled to room temperature and partitioned between ethyl acetate(20 mL) and water (10 mL). The organics were washed (brine), dried(Na₂SO₄), filtered, concentrated under vacuum, and purified on silicagel (elution with 100:1 hexane/EtOAc) to provide 3.28 g of compound 5(96% yield) as a yellow liquid.

Synthesis of 2-Benzyloxy-1-methylpyridinium triflate, Compound 1 asShown in FIG. 8 and FIG. 12

To a cold (0° C.) solution of 2-benzyloxypyridine (compound 5) (100 mg,0.54 mmol) in toluene (0.540 mL) was added methyltrifluoromethanesulfonate (64 L, 0.57 mmol). The mixture was allowed towarm to room temperature, which resulted in the formation of a whitecrystalline precipitate. After 40 min, the volatiles were removed invacuo, providing 0.172 g (91% yield) of 1 as a white microcrystallinesolid, mp: 82-86° C. A similar large-scale experiment afforded 6.52 g(86% yield) of 1 as a white solid, which was collected by filtration ofthe crude reaction mixture through a fritted glass funnel, followed bydrying under vacuum. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J=7.8 Hz, 1H),8.34 (apparent t, J=8.3 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.53-7.42 (m,6H), 5.58 (s, 2H), 4.13 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) 159.6, 148.0, 143.8, 132.5, 129.6, 129.1, 128.5,119.0, 112.1, 74.5, 42.0. HRMS (ESI⁺) found 200.10704 (M-OTf)⁺ (calcdfor C₁₃H₁₄NO⁺: 200.1075).

Another, perhaps more traditional formula depicting the compound of theinvention (compound 1 shown in FIGS. 8 and 12) is as follows:

Standard Procedure for Benzylation of Alcohols (2→3).

A mixture of pyridinium triflate 1 (100 mg, 0.29 mmol), benzotrifluoride(PhCF₃, 0.29 mL), MgO (11.5 mg, 0.29 mmol, vacuum-dried), and alcohol 2(0.14 mmol) was heated at 83° C. for 1 day. The reaction mixture wascooled to room temperature and filtered through Celite®. The filtratewas concentrated under vacuum and purified on silica gel to yield benzylether 3 (see Table 5), admixed with varying amounts of Bn₂O.

Benzylation of Diethylene Glycol Monomethyl Ether (Monoglyme, Compound2d)

A mixture of pyridinium triflate 1 (581 mg, 1.67 mmol), benzotrifluoride(PhCF₃, 1.7 mL), MgO (67 mg, 1.7 mmol), and compound 2d (100 mg, 0.83mmol) was subjected to the standard procedure to afford 0.163 g (93%) ofdiethylene glycol benzyl methyl ether (compound 3d) as a pale yellowliquid, which exhibited spectroscopic properties consistent with thereported data.

Benzylation of 1-Adamantanol (2i).

A mixture of pyridinium triflate 1 (100 mg, 0.29 mmol), benzotrifluoride(PhCF₃, 0.29 mL), MgO (11.5 mg, 0.29 mmol), and 28 (21,8 mg, 0.14 mmol)was subjected to the standard procedure to afford 0.0363 g of a yellowoil, which was determined by ¹H NMR analysis to consist of 8.7 mg ofBn₂O and 0.0276 g (80%) of 1-benzyloxyadamantane (3i). Spectroscopicanalysis was consistent with the data reported previously for 3i.

Benzylation of Trimethylsilylethanol.

In order to show the advantage of the present invention and,specifically of compound 1 herein, an experiment was conducted usingtrimethylsilylethanol (compound 13) as a substrate for benzylation. Notethat compound 13 is subjected to Peterson elimination under acidic (orbasic) conditions; see Ager, D. J. in Org. React., 1990, 38, 1.Benzylation of trimethylsilylethanol, that is, the conversion 13→14 asshown in FIG. 13, has not been previously reported. Reaction of 13 with1 proceeded to complete conversion with no evidence of decomposition,whereas a similar experiment using benzyl trichloroacetimidate yieldedno evidence of the desired product (compound 14). This is supported bythe ¹H NMR spectra obtained of the crude product mixtures after aqueousworkup.

In summary, the present invention provides compounds and methods forarylmethylation (benzylation) as protection for alcohol groups duringchemical synthesis. The protection is easily and economically effectedand reactants are also equally easily deprotected once the syntheticprocess has been completed.

Accordingly, in the drawings and specification, there have beendisclosed a typical preferred embodiment of the invention, and althoughspecific terms are employed, the terms are used in a descriptive senseonly and not for purposes of limitation. The invention has beendescribed in considerable detail with specific reference to theseillustrated embodiments. It will be apparent, however, that variousmodifications and changes can be made within the spirit and scope of theinvention as described in the foregoing specification and as defined inthe appended claims.

TABLE 1 Protection of phenols and alcohols as PSB ethers.

PSB ether (% entry PSB-X alcohol conditions^(a) yield) 1 1a 2a A 3a(74)   2 1b B — 3 C 3a (70)   4 1a 2b A 3b (96)   5 1b 2c C 3c (80-83) 6B — 7 2d C 3d (50)   8 2e C 3e (38)   ^(a)Conditions: A: PPh₃, DEAD,CH₂Cl₂; B: K₂CO₃/TBAI, Cs₂CO₃, or NaH, DMF; C: Ag₂O, CH₂Cl₂

TABLE 2 Cleavage of PSB ethers.

PHB alcohol PSB ether (% (% entry ether conditions^(a) yield) yield) 13a D — 2a (89) 2 3b — 2b (86) 3 3c i. D 4c (87) 2c (99) 4 3d ii. FeCl₃4d (84) 2d (97) 5 3e 4e (85) 2e (94) 6 3c i. E; ii. DDQ 4c (99) 2c (90)7 3d i. E; ii FeCl₃ 4d (99) 2d (97) 8 3e F — 2c (88) ^(a)Conditions: D:K₂CO₃, KF₂•H₂O, 30% aqueous H₂O₂, THF/MeOH, 50° C.; ¹⁶E: TBAF, tBuOOH,DMF, 70° C.; F: H₂, 10% Pd/C.

TABLE 3 Initial optimization

equiv. entry acid scavenger 1 yield^(b,c) 1 2,6-lutidine 1.0 43% (57%) 2Hünig's base 1.0 29% (39%) 3 K₂CO₃ 1.0 68% (93%) 4 MgO 1.0 78% (93%) 5  1.0 53% (87%) 6 MgO 2.0 76% (85%) 7 MgO 3.0 87%     ^(a)See supportingInformation for details. ^(b)Value in parenthesis refers to calculatedyield based on recovered alcohol. ^(c)Estimated by ¹H NMR spectroscopy.

TABLE 4 Screening for optimal solvent

entry solvent yield^(a) 1 l,2-dichloroethane 67% (DCE) 2 nitromethane(low) 3 acetonitrile — 4 N-methyl-2-pyrrolidinone (NMP) — 5 toluene 91%6 benzene 93% 7 chlorobenzene >95%  8 benzotrifluoride (PhCF₃) >95% ^(a)Estimated by ¹HNMR spectroscopy

TABLE 5 Scope and limitations

entry ROH (2) ROBn (3) yield^(a) 1

>95%   2^(b)

>95%  3

>95%  4

n.d.^(c) 5

 93%^(d) 6

85% 7

83% 8

88% 9

n.d.^(c) 10 

80% 11 

44% 12 

65% ^(a)Yields are estimated by ¹H NMR specoscopy, unless otherwiseindicated. ^(b)Reagent 1 stored for three months at room temperaturebefore use. ^(c)Not determined. ^(d)Isolated yield of pure product.^(e)Unreacted 2k also observed in crude product mixture.

1. A method of making 2-benzyloxy-1-methylpyridinium triflate, themethod comprising: adding methyl trifluoromethanesulfonate to a coldsolution of 2-benzyloxypyridine in toluene; and reacting the solution atambient temperature to generate a precipitate of2-benzyloxy-1-methylpyridinium triflate.
 2. A method of synthesizing2-benzyloxy-1-methylpyridinium triflate, the method comprising reactingmethyl trifluoromethanesulfonate with 2-benzyloxypyridine in toluene togenerate a precipitate of 2-benzyloxy-1-methylpyridinium triflate. 3.The method of claim 1 further comprising separating the precipitate anddrying the separated precipitate.
 4. The compound2-benzyloxy-1-methylpyridinium triflate made according to the method ofclaim
 1. 5. The compound 2-benzyloxy-1-methylpyridinium triflate madeaccording to the method of claim
 2. 6. A compound having the formula

wherein Me comprises a methyl group, Bn comprises a benzyl group and Tfcomprises a trifluoro group.